Viral escape in the CNS with multidrug-resistant HIV-1.

Introduction: HIV-1 viral escape in the cerebrospinal fluid (CSF) despite viral suppression in plasma is rare [1,2]. We describe the case of a 50-year-old HIV-1 infected patient who was diagnosed with HIV-1 in 1995. Antiretroviral therapy (ART) was started in 1998 with a CD4 T cell count of 71 cells/ìL and HIV-viremia of 46,000 copies/mL. ART with zidovudine (AZT), lamivudine (3TC) and efavirenz achieved full viral suppression. After the patient had interrupted ART for two years, treatment was re-introduced with tenofovir (TDF), emtricitabin (FTC) and ritonavir boosted atazanavir (ATVr). This regimen suppressed HIV-1 in plasma for nine years and CD4 cells stabilized around 600 cells/ìL. Since July 2013, the patient complained about severe gait ataxia and decreased concentration. Materials and Methods: Additionally to a neurological examination, two lumbar punctures, a cerebral MRI and a neuropsycological test were performed. HIV-1 viral load in plasma and in CSF was quantified using Cobas TaqMan HIV-1 version 2.0 (Cobas Ampliprep, Roche diagnostic, Basel, Switzerland) with a detection limit of 20 copies/mL. Drug resistance mutations in HIV-1 reverse transcriptase and protease were evaluated using bulk sequencing. Results: The CSF in January 2014 showed a pleocytosis with 75 cells/ìL (100% mononuclear) and 1,184 HIV-1 RNA copies/mL, while HIV-1 in plasma was below 20 copies/mL. The resistance testing of the CSF-HIV-1 RNA showed two NRTI resistance-associated mutations (M184V and K65R) and one NNRTI resistance-associated mutation (K103N). The cerebral MRI showed increased signal on T2-weighted images in the subcortical and periventricular white matter, in the basal ganglia and thalamus. Four months after ART intensification with AZT, 3TC, boosted darunavir and raltegravir, the pleocytosis in CSF cell count normalized to 1 cell/ìL and HIV viral load was suppressed. The neurological symptoms improved; however, equilibrium disturbances and impaired memory persisted. The neuro-psychological evaluation confirmed neurocognitive impairments in executive functions, attention, working and nonverbal memory, speed of information processing, visuospatial abilities and motor skills. Conclusions: HIV-1 infected patients with neurological complaints prompt further investigations of the CSF including measurement of HIV viral load and genotypic resistance testing since isolated replication of HIV with drug resistant variants can rarely occur despite viral suppression in plasma. Optimizing ART by using drugs with improved CNS penetration may achieve viral suppression in CSF with improvement of neurological symptoms.

Assessing efficacy of different nucleos(t)ide backbones in NNRTI-containing regimens in the Swiss HIV Cohort Study.

BACKGROUND The most recommended NRTI combinations as first-line antiretroviral treatment for HIV-1 infection in resource-rich settings are tenofovir/emtricitabine, abacavir/lamivudine, tenofovir/lamivudine and zidovudine/lamivudine. Efficacy studies of these combinations also considering pill numbers, dosing frequencies and ethnicities are rare. METHODS We included patients starting first-line combination ART (cART) with or switching from first-line cART without treatment failure to tenofovir/emtricitabine, abacavir/lamivudine, tenofovir/lamivudine and zidovudine/lamivudine plus efavirenz or nevirapine. Cox proportional hazards regression was used to investigate the effect of the different NRTI combinations on two primary outcomes: virological failure (VF) and emergence of NRTI resistance. Additionally, we performed a pill burden analysis and adjusted the model for pill number and dosing frequency. RESULTS Failure events per treated patient for the four NRTI combinations were as follows: 19/1858 (tenofovir/emtricitabine), 9/387 (abacavir/lamivudine), 11/344 (tenofovir/lamivudine) and 45/1244 (zidovudine/lamivudine). Compared with tenofovir/emtricitabine, abacavir/lamivudine had an adjusted HR for having VF of 2.01 (95% CI 0.86-4.55), tenofovir/lamivudine 2.89 (1.22-6.88) and zidovudine/lamivudine 2.28 (1.01-5.14), whereas for the emergence of NRTI resistance abacavir/lamivudine had an HR of 1.17 (0.11-12.2), tenofovir/lamivudine 11.3 (2.34-55.3) and zidovudine/lamivudine 4.02 (0.78-20.7). Differences among regimens disappeared when models were additionally adjusted for pill burden. However, non-white patients compared with white patients and higher pill number per day were associated with increased risks of VF and emergence of NRTI resistance: HR of non-white ethnicity for VF was 2.85 (1.64-4.96) and for NRTI resistance 3.54 (1.20-10.4); HR of pill burden for VF was 1.41 (1.01-1.96) and for NRTI resistance 1.72 (0.97-3.02). CONCLUSIONS Although VF and emergence of resistance was very low in the population studied, tenofovir/emtricitabine appears to be superior to abacavir/lamivudine, tenofovir/lamivudine and zidovudine/lamivudine. However, it is unclear whether these differences are due to the substances as such or to an association of tenofovir/emtricitabine regimens with lower pill burden.

Determinants of Weight Evolution Among HIV-Positive Patients Initiating Antiretroviral Treatment in Low-Resource Settings.

BACKGROUND In resource-limited settings, clinical parameters, including body weight changes, are used to monitor clinical response. Therefore, we studied body weight changes in patients on antiretroviral treatment (ART) in different regions of the world. METHODS Data were extracted from the "International Epidemiologic Databases to Evaluate AIDS," a network of ART programmes that prospectively collects routine clinical data. Adults on ART from the Southern, East, West, and Central African and the Asia-Pacific regions were selected from the database if baseline data on body weight, gender, ART regimen, and CD4 count were available. Body weight change over the first 2 years and the probability of body weight loss in the second year were modeled using linear mixed models and logistic regression, respectively. RESULTS Data from 205,571 patients were analyzed. Mean adjusted body weight change in the first 12 months was higher in patients started on tenofovir and/or efavirenz; in patients from Central, West, and East Africa, in men, and in patients with a poorer clinical status. In the second year of ART, it was greater in patients initiated on tenofovir and/or nevirapine, and for patients not on stavudine, in women, in Southern Africa and in patients with a better clinical status at initiation. Stavudine in the initial regimen was associated with a lower mean adjusted body weight change and with weight loss in the second treatment year. CONCLUSIONS Different ART regimens have different effects on body weight change. Body weight loss after 1 year of treatment in patients on stavudine might be associated with lipoatrophy.

Hepatitis B Infection, Viral Load and Resistance in HIV-Infected Patients in Mozambique and Zambia.

BACKGROUND Few data on the virological determinants of hepatitis B virus (HBV) infection are available from southern Africa. METHODS We enrolled consecutive HIV-infected adult patients initiating antiretroviral therapy (ART) at two urban clinics in Zambia and four rural clinics in Northern Mozambique between May 2013 and August 2014. HBsAg screening was performed using the Determine® rapid test. Quantitative real-time PCR and HBV sequencing were performed in HBsAg-positive patients. Risk factors for HBV infection were evaluated using Chi-square and Mann-Whitney tests and associations between baseline characteristics and high level HBV replication explored in multivariable logistic regression. RESULTS Seventy-eight of 1,032 participants in Mozambique (7.6%, 95% confidence interval [CI]: 6.1-9.3) and 90 of 797 in Zambia (11.3%, 95% CI: 9.3-13.4) were HBsAg-positive. HBsAg-positive individuals were less likely to be female compared to HBsAg-negative ones (52.3% vs. 66.1%, p<0.001). Among 156 (92.9%) HBsAg-positive patients with an available measurement, median HBV viral load was 13,645 IU/mL (interquartile range: 192-8,617,488 IU/mL) and 77 (49.4%) had high values (>20,000 UI/mL). HBsAg-positive individuals had higher levels of ALT and AST compared to HBsAg-negative ones (both p<0.001). In multivariable analyses, male sex (adjusted odds ratio: 2.59, 95% CI: 1.22-5.53) and CD4 cell count below 200/μl (2.58, 1.20-5.54) were associated with high HBV DNA. HBV genotypes A1 (58.8%) and E (38.2%) were most prevalent. Four patients had probable resistance to lamivudine and/or entecavir. CONCLUSION One half of HBsAg-positive patients demonstrated high HBV viremia, supporting the early initiation of tenofovir-containing ART in HIV/HBV-coinfected adults.

Dually Active HIV/HBV Antiretrovirals Protect Against Incident Hepatitis B Infections: Potential for Prophylaxis.

BACKGROUND  Hepatitis-B virus (HBV) has a detrimental effect on HIV natural course, and HBV vaccination is less effective in the HIV infected. We examine the protective effect of dually active antiretroviral therapy (DAART) for HIV/HBV (Tenofovir/Lamivudine/Emtricitabine) in a large cohort encompassing heterosexuals, men-who-have-sex-with-men (MSM), and intravenous drug users (IDU), who are HIV-infected yet susceptible to HBV, with comprehensive follow-up data about risky behavior and immunological profile. METHODS  We defined an incident HBV infection as the presence of any of HBV serological markers (HBsAg/AntiHBc/HBV-DNA) following a negative baseline AntiHBc test. Patients with positive AntiHBs were excluded. Cox proportional hazard models were utilized, with an incident case of HBV infection as the outcome variable. RESULTS  We analyzed 1,716 eligible patients from the Swiss HIV Cohort Study with 177 incident HBV cases. DAART was negatively associated with incident HBV infection (hazard ratio 0.4, 95%CI 0.2-0.6). This protective association was robust to adjustment (0.3, 0.2-0.5) for condomless sex, √CD4 count, drug use, and patients' demographics. Condomless sex (1.9,1.4-2.6), belonging to MSM (2.7,1.7-4.2) or IDU (3.8,2.4-6.1) were all associated with higher HBV hazard. CONCLUSIONS  Our study suggests that DAART, independently of CD4 count and risky behavior, has a potentially strong public health impact including pre-exposure prophylaxis of HBV co-infection.

Mechanistic Models of Anti-HIV Microbicide Drug Delivery

A new modality for preventing HIV transmission is emerging in the form of topical microbicides. Some clinical trials have shown some promising results of these methods of protection while other trials have failed to show efficacy. Due to the relatively novel nature of microbicide drug transport, a rigorous, deterministic analysis of that transport can help improve the design of microbicide vehicles and understand results from clinical trials. This type of analysis can aid microbicide product design by helping understand and organize the determinants of drug transport and the potential efficacies of candidate microbicide products.

Microbicide drug transport is modeled as a diffusion process with convection and reaction effects in appropriate compartments. This is applied here to vaginal gels and rings and a rectal enema, all delivering the microbicide drug Tenofovir. Although the focus here is on Tenofovir, the methods established in this dissertation can readily be adapted to other drugs, given knowledge of their physical and chemical properties, such as the diffusion coefficient, partition coefficient, and reaction kinetics. Other dosage forms such as tablets and fiber meshes can also be modeled using the perspective and methods developed here.

The analyses here include convective details of intravaginal flows by both ambient fluid and spreading gels with different rheological properties and applied volumes. These are input to the overall conservation equations for drug mass transport in different compartments. The results are Tenofovir concentration distributions in time and space for a variety of microbicide products and conditions. The Tenofovir concentrations in the vaginal and rectal mucosal stroma are converted, via a coupled reaction equation, to concentrations of Tenofovir diphosphate, which is the active form of the drug that functions as a reverse transcriptase inhibitor against HIV. Key model outputs are related to concentrations measured in experimental pharmacokinetic (PK) studies, e.g. concentrations in biopsies and blood. A new measure of microbicide prophylactic functionality, the Percent Protected, is calculated. This is the time dependent volume of the entire stroma (and thus fraction of host cells therein) in which Tenofovir diphosphate concentrations equal or exceed a target prophylactic value, e.g. an EC50.

Results show the prophylactic potentials of the studied microbicide vehicles against HIV infections. Key design parameters for each are addressed in application of the models. For a vaginal gel, fast spreading at small volume is more effective than slower spreading at high volume. Vaginal rings are shown to be most effective if inserted and retained as close to the fornix as possible. Because of the long half-life of Tenofovir diphosphate, temporary removal of the vaginal ring (after achieving steady state) for up to 24h does not appreciably diminish Percent Protected. However, full steady state (for the entire stromal volume) is not achieved until several days after ring insertion. Delivery of Tenofovir to the rectal mucosa by an enema is dominated by surface area of coated mucosa and whether the interiors of rectal crypts are filled with the enema fluid. For the enema 100% Percent Protected is achieved much more rapidly than for vaginal products, primarily because of the much thinner epithelial layer of the mucosa. For example, 100% Percent Protected can be achieved with a one minute enema application, and 15 minute wait time.

Results of these models have good agreement with experimental pharmacokinetic data, in animals and clinical trials. They also improve upon traditional, empirical PK modeling, and this is illustrated here. Our deterministic approach can inform design of sampling in clinical trials by indicating time periods during which significant changes in drug concentrations occur in different compartments. More fundamentally, the work here helps delineate the determinants of microbicide drug delivery. This information can be the key to improved, rational design of microbicide products and their dosage regimens.

Development of water-soluble polyanionic carbosilane dendrimers as novel and highly potent topical anti-HIV-2 microbicides

This is the author’s version of a work that was accepted for publication in Nanoscale.

Profilaxia de pré-exposição da infeção por VIH

"Objetivos: Rever os conhecimentos existentes sobre a Profilaxia de Pré-Exposição (PrEP) na prevenção da infeção por VIH, nomeadamente o papel da circuncisão médica masculina, dos antirretrovirais de administração oral e dos microbicidas tópicos. Fontes de Dados: Artigos publicados na PubMed e informação presente na base de dados de ensaios clínicos (www.clinicaltrials.gov). Métodos: Revisão compreensiva da literatura. Resultados: A circuncisão médica masculina é uma estratégia preventiva que demonstra uma eficácia de 48 a 60 por cento. A utilização de antirretrovirais por via oral como prevenção da infeção por VIH tem eficácia variável que depende essencialmente da taxa de adesão (62,2 por cento no estudo TDF2, com adesão de 84,1 por cento; 44 por cento no estudo iPrEx, com adesão de <50 por cento; 48,9 por cento no estudo Bangkok, com adesão de 67 por cento; 67-75 por cento no estudo Partners PrEP, com adesão de 82 por cento; e 6 por cento no estudo FEM-PrEP, com adesão de 40 por cento). Em relação aos microbicidas tópicos, o estudo CAPRISA 004 demonstrou que um gel de tenofovir a 1 por cento pode reduzir de forma significativa (≥39 por cento, dependendo da taxa de adesão) a taxa de infeção por VIH. O gel PRO2000 causou uma redução não significativa da taxa de infeção por VIH (30 por cento). Conclusões: A circuncisão médica masculina é uma intervenção custo-efectiva, mas requer estratégias de comunicação cuidadosas para ser bem-sucedida. A PrEP utilizando antirretrovirais é igualmente eficaz, mas está muito dependente da adesão à terapêutica por parte do indivíduo. No que respeita aos microbicidas, o gel de tenofovir a 1 por cento é atualmente a única opção promissora."